Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3β. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with βTrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2α, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent β-cell death under ER stress conditions.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic intestinal inflammation. Recent research has highlighted the significant interplay between IBD pathogenesis and circadian rhythms. This review synthesizes current evidence regarding circadian regulation in IBD, covering three main areas: (1) circadian rhythms in intestinal physiology, (2) circadian disruption patterns in IBD patients, and (3) the role of clock genes in IBD pathogenesis. We discuss how these findings may inform novel chronotherapeutic approaches for IBD treatment. Future research directions that could facilitate translation of chronobiological insights into clinical applications are also explored.

Sudachitin, a member of the flavonoid family, reportedly improves glucose metabolism after long-term administration, but details of the underlying mechanisms are unknown. We found that Sudachitin approximately doubles insulin secretion under high glucose concentrations in mouse pancreatic islets and MIN6 cells. When Sudachitin was orally administered to mice, early-phase insulin secretion was increased and a 30 % reduction in blood glucose levels was demonstrated 30 min after glucose loading. Insulin tolerance tests also showed Sudachitin to increase systemic insulin sensitivity. Additionally, we observed that Sudachitin raised intracellular cAMP levels in pancreatic islets. Phosphodiesterase (PDE) activity assays revealed Sudachitin to inhibit PDE activity and computer simulations predicted a high binding affinity between PDEs and Sudachitin. These findings suggest that Sudachitin enhances both insulin secretion and insulin sensitivity via an increase in intracellular cAMP resulting from PDE inhibition. These insights may facilitate understanding the mechanisms underlying the regulation of glucose metabolism by Sudachitin and other isoflavones.

Background/Objectives: Diabetes-related pancreatic changes on MRI remain unclear. Thus, we evaluated the pancreatic changes on MRI in patients with both type 1 diabetes (T1D) and type 2 diabetes (T2D) using multiparametric MRI. Methods: This prospective study involved patients with T1D or T2D who underwent upper abdominal 3-T MRI. Additionally, patients without impaired glucose metabolism were retrospectively included as a control. The imaging data included pancreatic anteroposterior (AP) diameter, pancreas-to-muscle signal intensity ratio (SIR) on fat-suppressed T1-weighted image (FS-T1WI), apparent diffusion coefficient (ADC) value, T1 value on T1 map, proton density fat fraction (PDFF), and mean secretion grade of pancreatic juice flow on cine-dynamic magnetic resonance cholangiopancreatography (MRCP). The MR measurements were compared using one-way analysis of variance and the Kruskal–Wallis test. Results: Sixty-one patients with T1D (n = 7) or T2D (n = 54) and 21 control patients were evaluated. The pancreatic AP diameters were significantly smaller in patients with T1D than in patients with T2D (p < 0.05). The average SIR on FS-T1WI was significantly lower in patients with T1D than in controls (p < 0.001). The average ADC and T1 values of the pancreas were significantly higher in patients with T1D than in patients with T2D (p < 0.01) and controls (p < 0.05). The mean secretion grade of pancreatic juice flow was significantly lower in patients with T1D than in controls (p = 0.019). The average PDFF of the pancreas was significantly higher in patients with T2D than in controls (p = 0.029). Conclusions: Patients with T1D had reduced pancreas size, increased pancreatic T1 and ADC values, and decreased pancreatic juice flow on cine-dynamic MRCP, whereas patients with T2D had increased pancreatic fat content.

Rising nicotinamide adenine dinucleotide (NAD+) levels mitigate the onset and progression of age-related diseases including metabolic disorders. Several studies have demonstrated that NAD+ levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake and thereby prevent metabolic disorders. However, the acute effects of NMN administration on metabolism remain unclear. We observed metabolic dynamics after a single bolus injection of NMN. Sirt1 and Nampt mRNA levels were increased in the liver suggesting that intracellular NAD+ increased after injection. During OGTT, glucose tolerance and insulin secretion did not change significantly in response to NMN administration, while during ITT, increased insulin sensitivity was observed in muscle. NMN administration decreased serum non-esterified free fatty acid (NEFA) concentrations, which would presumably be responsible for the increased muscle insulin sensitivity. Furthermore, NMN administration reduced the respiratory quotient, confirming that NMN promotes utilization of lipids as an energy source. Our data demonstrate acute effects of NMN on metabolism and raise the possibility of NMN as a treatment for metabolic disorders.